This invention relates to inotrope drugs, which can increase the strength of a heartbeat. Such drugs are often used after cardiac surgery, if a patient's heart is struggling to regain adequate strength after the patient has been taken off of a cardiopulmonary bypass machine.
Patients are often put on cardiopulmonary bypass (CPB) for heart surgery (including coronary artery bypass, heart valve repair or replacement, surgery to correct an arryhthmia, heart transplants, etc.), and, less frequently, for other types of surgery as well, including various types of pulmonary or brain surgery. The equipment and techniques involved in CPB surgery are described in numerous medical textbooks and articles, including Surgery of the Chest (Sabiston and Spencer, eds., Saunders Publ., Philadelphia) and Cardiac Surgery by Kirklin and Barrett-Boyes and various articles cited therein.
As is well-known to cardiac surgeons, some patients who undergo CPB surgery encounter serious difficulty in regaining a sufficiently strong and stable heartbeat when they are "weaned" from the CPB pumping machine. Such problems are especially common among elderly patients, and among patients who suffer from severe or prolonged heart disease. Various mechanical methods and equipment can be used to assist the heart, including implantation of a pacemaker to stabilize the frequency of a heartbeat, and, in extreme cases, temporary implantation of a so-called "left ventricular assist" (LVAD) pumping device.
Various drugs (generally referred to as "inotropes" or "cardiotonic" agents) are also widely used to stimulate the heart muscle and increase the strength of a heartbeat, after cardiac surgery. The most widely used inotrope drugs include digitalis glycosides (also called digoxins), various inotropic catecholamines, including epinephrin and norepinephrin (also called adrenaline and noradrenaline), dopamine, and dobutamine, and a drug called amrinone lactate.
All of these previously known inotrope drugs suffer from various risks, limitations, and adverse side effects, and they are not administered unless it becomes apparent in a specific patient that such drugs are needed to deal with a medical crisis. In general, they all interact directly with neuronal and/or hormonal receptors (primarily beta receptors, on heart cells), triggering various types of artificially-stimulated excitation of the activated cells and tissue. Therefore, such inotrope drugs alter and disrupt the desirable homeostatic balances and equilibria that a heart tries to maintain.
In particular, all previously known inotrope drugs have an undesirable and potentially dangerous side effect: they increase the rate of the heartbeat (the number of beats per minute). This imposes a severe form of stress on an already-stressed heart, and such drugs are dangerous to the point of lethal in substantial numbers of patients; even a slight overdose of a conventional inotrope can drive an already weakened cardiac surgery patient into cardiac failure and collapse.
By contrast, a better inotropic drug would increase the strength of the heartbeat (as measured by indices such as volume of blood output per heartbeat stroke), without increasing the heartbeat rate (i.e., without causing the heart to beat faster.
A second undesired and dangerous aspect of previously known inotrope drugs is that their useful effects diminish fairly quickly over time; within about 3 days, the efficacy of any of these drugs drops to about half of what it was when treatment commenced. This drop of efficacy involves a form of drug tolerance that is usually known as "tachyphylaxis". It is especially dangerous, because all beta receptor agonists (which includes nearly all of the inotropic catecholamines) share this property. In other words, if dopamine is used as an initial inotrope, during the first days when someone's heart is not beating adequately after CPB surgery, then it will not help the patient to switch to some other catecholamine or other beta agonist when the dopamine efficacy drops off.
Even if a conventional inotrope drug works exactly as hoped during the first day or two after surgery, it can leave the heart in a compromised position as it wears off. Inotrope drugs are heart stimulants, pure and simple. Accordingly, giving a weakened patient an inotrope drug, after cardiac surgery, is comparable to giving a stimulant such as amphetamine (commonly called "speed") to someone who is exhausted, due to overexertion combined with lack of adequate food. The stimulant may offer a quick fix; it may help the person deal with a specific short-lived demand or deadline.
However, after the stimulant wears off, the person will be even more exhausted, and depleted. His/her need to rest and recover will be even more severe than it was, before he or she took the stimulant drug. Stimulants which increase the heartbeat rate can actually induce (precipitate) hypoxia and ischemia, in tissue that is already starved for oxygen; using stimulant drugs to force the heart to beat faster, shortly after bypass surgery, is like forcing a person to run sprints, shortly after that person has suffered a near-drowning accident.
Unlike a person suffering from severe exhaustion, a heart cannot go to sleep so it can rest, recover, and regain strength. It must continue beating actively, even when the patient is resting or sleeping. Accordingly, it is difficult and dangerous to subject a heart to the type of "double-tired" exhaustion that results from using stimulant drugs to drive the heart harder and faster while it is trying to recover from a severe ordeal.
As noted, all of the previously known inotropic drugs work by artificially stimulating certain hormonal or neuronal receptors (mainly beta receptors) on the heart. By contrast, FDP (the inotropic drug discussed below) works by an entirely different mechanism. Instead of triggering abnormally high activity in heart muscle by stimulating hormonal or neuronal receptors, it provides a completely safe and healthy form of nutrition for the heart muscle. By way of analogy, providing FDP to a struggling heart is like giving a good, nutritious, healthy meal (rather than dangerous hunger-suppressing amphetamines) to a starving person. Rather than masking symptoms and leading to even more severe forms of exhaustion, a good, nutritious, and healthy meal can help a starving man regain his strength and restore a safe and stable balance, after he has suffered through a severe ordeal.
That is the goal, and the result, of this invention.
Furthermore, unlike previously known inotropes, such as adrenalin or norepinephrin, FDP does not increase the heartbeat rate to abnormally high levels. The tests done to date indicate that FDP no statistically significant effects on heartbeat rate. Instead, it merely strengthens the heart, so that the "hemodynamic performance" of the heart during each heartbeat is improved, as indicated by the various measures described below.
Measures of Heart Performance
There are several indices that can be measured and/or calculated to evaluate the strength and condition of a heart. These indices, along with their abbreviations and units of measurement, are listed below. In all indices, LV refers to the left ventricle, while mm Hg is a pressure value, expressed as millimeters of a mercury column. These values can be measured and calculated as described in Grossman 1991.
CO--cardiac output, expressed as liters of blood pumped per minute.
CI--cardiac index, expressed as liters of blood pumped per minute, divided by the body surface area of the patient, in square meters.
SVI--stroke volume index, expressed as milliliters of blood pumped per heartbeat, divided by the body surface area of the patient, in square meters.
LVSP--left ventricular systolic pressure, expressed in mm Hg. This is a peak pressure generated during contraction of the left ventricle.
LVSWI--left ventricular stroke work index, expressed as grams-meters, divided by the body surface area of the patient in square meters.
LVEDP--left ventricular end diastolic pressure, expressed as mm Hg.
MAP--mean aortic pressure, expressed as mm Hg, indicates the pressure that contraction of the left ventricle is able to generate, averaged over an entire heartbeat.
PVR--pulmonary vascular resistance, expressed in dynes-seconds divided by cm.sup.5.
SVR--systemic vascular resistance, expressed as dynes-seconds divided by cm.sup.5.
MPAP--mean pulmonary artery pressure, expressed in mm Hg.
Fructose-1,6-Diphosphate (FDP)
Fructose-1,6-diphosphate (FDP) is a naturally occurring sugar-phosphate molecule, which is created and then quickly consumed as an intermediate during the series of reactions that make up glycolysis. As a short-lived intermediate that is quickly consumed, it normally is present in cells only at relatively low concentrations. It should be noted that some scientists refer to FDP as fructose-1,6-biphosphate, or fructose-1,6-bisphosphate.
The 1,6-isomer of fructose diphosphate, which contains phosphate groups bonded to the #1 and #6 carbon atoms of the fructose molecule, is the only isomer of interest herein. Other isomers (such as fructose-2,6-diphosphate) are not relevant herein, and are excluded from any references herein to FDP or fructose diphosphate.
Numerous medical and scientific articles have suggested that FDP might potentially be useful as a medical treatment for medical crises such as strokes, cardiac arrest, heart attack, suffocation, loss of blood due to injury, shooting, or stabbing, etc. Such articles include Markov et al 1980, 1986, and 1987, Brunswick et al 1982, Marchionni et al 1985, Farias et al 1986, Grandi et al 1988, Zhang et al 1988, Lazzarino et al 1989 and 1992, Janz et al 1991, Hassinen et al 1991, Cargnoni et al 1992, and Munger et al 1994. Relevant U.S. patents include U.S. Pat. Nos. 4,546,095 (Markov 1985), 4,703,040 (Markov 1987), and 4,757,052 (Markov 1988).
Despite all of these published articles and patents, which stretch back roughly 20 years, a high degree of skepticism and reluctance still exists regarding FDP use to treat ischemia or hypoxia. Except for a few small and very limited clinical trials, FDP simply is not used or prescribed by any practicing physicians, except possibly in a few foreign countries such as China and Italy.
The absence of actual use of FDP on patients is believed to be due to a number of factors, including the following:
(1) FDP is a diphosphate with a strong negative charge; accordingly, it is generally assumed by doctors and researchers that its highly-charged nature will prevent it from entering cells in substantial quantities. Since energy metabolism and glycolysis occur inside cells, it is generally assumed that FDP will not get to the relevant site in sufficient quantities to do any substantial good.
(2) It is also believed that FDP has a very short half-life in the blood, and will effectively disappear from the blood within a few minutes after injection or infusion.
(3) The amount of energy generated during glycolysis (i.e., the conversion of glucose to pyruvic acid) is only a small fraction of the energy generated by the aerobic (Krebs Cycle) oxidation of pyruvic acid to form carbon dioxide and water. Therefore, under conditions of tissue ischemia or hypoxia, where an oxygen deficit blocks aerobic conversion, it is generally assumed that FDP infusion would be insufficient to supplement ATP levels to a degree that can significantly aid cell survival.
(4) It is also generally assumed that under conditions of ischemia or hypoxia, where inadequate oxygen is present, an injection of FDP would likely lead to increases in lactic acid levels. This would be harmful, rather than beneficial.
(5) Contrary to the articles cited above, which report that FDP may have beneficial effects in certain types of lab tests, a number of other articles have reported that FDP had no beneficial effects in other studies. Examples of these negative articles include Eddy et al 1981, Pasque et al 1984, Tortosa et al 1993, and Angelos et al 1993.
For these and other reasons, it appears that little if any effort has been directed by the pharmaceutical industry toward developing FDP as a useful drug. Under the laws enforced by the U.S. Food and Drug Administration (and by comparable agencies in other countries, such as the Medicines Control Agency, in Great Britain), FDP cannot be sold in the United States for administration to human patients by physicians. With the possible exception of a few small clinical trials, FDP simply is not administered to any patients, on any sort of routine basis, regardless of how desperate their plight may be following a stroke, cardiac arrest, shooting, stabbing, etc.
Currently, there are only two known preparations of FDP which are commercially available anywhere in the world, other than research reagents that are sold in gram or milligram quantities by specialty chemical companies. One of these preparations is a non-sterile bulk powder, manufactured in Germany by Boehringer Mannheim. This material was purchased by the assignee (Cypros Pharmaceutical Corporation, of Carlsbad, Calif.) and used as a starting reagent to prepare the sterilized injectable formulations described herein.
The other commercially available FDP formulation is a lyophilized preparation that is manufactured in Italy by a company called Biochemica Foscama. To the best of the Applicant's knowledge and belief, it is manufactured by steps that including the following: (1) pouring a large batch of an aqueous mixture of FDP into a large, flat tray; (2) freezing the mixture and subjecting it to a vacuum, to remove the water, thereby creating a large solidified cake; (3) grinding or milling the large cake into small particles; (4) loading the ground-up particles into small vials; and, (5) sealing the vials. This process is not well suited for creating a sterile preparation for injection into humans; a process that uses large machinery to handle and manipulate a large cake, pass it through a device which grinds it up into small particles, pass the particles through various routing and funnelling devices in order to load those particles into small vials, and then seal the vials, creates numerous risks which seriously jeopardize the sterility of the resulting final product.
It should also be noted that if non-sterile FDP is loaded into a sealed vial, it cannot be subsequently treated by a "terminal sterilization" process, such as autoclaving or ionizing radiation. Those types of terminal (post-sealing) sterilization treatments would seriously degrade the chemical quality of the FDP in the sealed vials.
In addition to the two FDP preparations that are currently available from companies in Germany and Italy, as discussed above, several other patents have been issued during the last few years which describe methods for synthesizing or purifying FDP. The synthesis methods usually involve microbes which will convert glucose into FDP, if provided with glucose and a phosphate donor under proper fermentation conditions; these include Chinese patent 1,089,654 A (Yin, 1994) and U.S. Pat. Nos. 4,530,902 (Perri et al 1985) and 5,094,947 (Nakajima et al, 1991). The purification patents usually involve ion exchange chromatography; see U.S. Pat. Nos. 4,575,549 (Diana et al, 1986; apparently equivalent to German patent DE 3,446,927) and 5,434,255 (Katayama et al, 1995; apparently equivalent to Japanese patent JP 05271269 A2) as well as Chinese patents 1,089,615 A (Ying et al 1994) and 1,089,616 A (Ouyang et al 1994).
However, to the best of the Applicant's knowledge and belief, none of the recently developed methods for preparing FDP have yet culminated in any FDP preparations that are commercially available. Despite all of the published medical articles which stretch back roughly twenty years, a high degree of skepticism and reluctance still exists, regarding the medical use of FDP in humans. Except for a few very small and limited clinical trials, FDP simply is not used or prescribed by any practicing physicians, except possibly in a few foreign countries such as China and Italy.
Accordingly, one object of the subject invention is to provide a better cardiac inotrope for patients who are recovering from surgery which involved cardiopulmonary bypass. This improved and desired inotrope should strengthen and help stabilize the heartbeat, but it should not increase the heartbeat rate, and it should not have any other undesired side effects.
Another object of the subject invention is to disclose that FDP can be used as a safe and effective cardiac inotrope drug, for people emerging from surgery which required cardiopulmonary bypass.
Another object of the subject invention is to disclose that when FDP is used as a cardiac inotrope drug after surgery involving cardiopulmonary bypass, it provides a virtually ideal combination of desired activities coupled with an apparently complete absence of any undesired side effects.
These and other objects of the invention will become more apparent through the following summary, drawings, and description of the preferred embodiments.